Missing heritabilityClinical challenge <a href= Genetic Heterogeneitythe same gene with different functions. http://www.the-scientist.com/?articles.view/articleNo/45316/title/Same-Gene--Different-Functions/common variant common disease/rare variant rare disease/common variant rare disease/rare variant common diseaseSome regions have not been coverage by ExAC , maybe should switch to genomAD once it's available. Phenocentrol, Endeavour, Global Alliance for genomics or other phenotype matching platforms to merge WES or WGShttp://www.nature.com/news/exac-project-pins-down-rare-gene-variants-1.20425, only 4.6% variants are true. multiple testing issue for Compound Heterozygous & PPI mutationDigenic and oligogenicDynamic Tissue specific expression & the expression in embrionic stage Another challenge is the phenotype definition. For rare congenital disease, some of the subjects may have two or more different medical conditions at the same time. Even the defined condition could have different severity. The easiest way is just to divide it as case and control subjects.https://ghr.nlm.nih.gov/primer/inheritance/penetranceexpressivity , ALS and Marfan syndrome : The same mutation with different phenotpye. Expressivity measures the extent to which a genotype shows its phenotypic expression. Moreover, both the penetrance and expressivity of different diseases can be partially explained by the action of gene modifiers. same mutation with various phenotype.